Histone deacetylase (HDAC) inhibitors have garnered considerable interest for the treatment of adult and pediatric malignant brain tumors. However, owing to their broad-spectrum nature and inability to effectively penetrate the blood-brain barrier, HDAC inhibitors have failed to provide substantial clinical benefit to patients with glioblastoma (GBM) to date. Moreover, global inhibition of HDACs results in widespread toxicity, highlighting the need for selective isoform targeting. Although no isoform-specific HDAC inhibitors are currently available, the second-generation hydroxamic acid–based HDAC inhibitor quisinostat possesses subnanomolar specificity for class I HDAC isoforms, particularly HDAC1 and HDAC2. It has been shown that HDAC1 is the essential HDAC in GBM. This study analyzed the neuropharmacokinetic, pharmacodynamic, and radiation-sensitizing properties of quisinostat in preclinical models of GBM. It was found that quisinostat is a well-tolerated and brain-penetrant molecule that extended survival when administered in combination with radiation in vivo. The pharmacokinetic-pharmacodynamic-efficacy relationship was established by correlating free drug concentrations and evidence of target modulation in the brain with survival benefit. Together, these data provide a strong rationale for clinical development of quisinostat as a radiosensitizer for the treatment of GBM.
Costanza Lo Cascio, Tigran Margaryan, Ernesto Luna-Melendez, James B. McNamara, Connor I. White, William Knight, Saisrinidhi Ganta, Zorana Opachich, Claudia Cantoni, Wonsuk Yoo, Nader Sanai, Artak Tovmasyan, Shwetal Mehta
We previously showed that ablation of tumor hypoxia can sensitize tumors to immune checkpoint blockade (ICB). Here, we used a Kras+/G12DTP53+/R172HPdx1-Cre (KPC) derived model of pancreatic adenocarcinoma (PDAC) to examine the tumor response and adaptive resistance mechanisms involved in response to two established methods of hypoxia-reducing therapy: the hypoxia-activated prodrug TH-302 and vascular endothelial growth factor receptor 2 (VEGFR-2) blockade. The combination of both modalities normalized tumor vasculature, increased DNA damage and cell death, and delayed tumor growth. In contrast to prior cancer models, the combination did not alleviate overall tissue hypoxia or sensitize these KPC tumors to ICB therapy despite qualitative improvements to the CD8 T cell response. Bulk-tumor RNA sequencing, flow cytometry, and adoptive myeloid cell transfer suggested that treated tumor cells increased their capacity to recruit granulocytic myeloid derived suppressor cells (G-MDSC) through CCL9 secretion. Blockade of the CCL9-CCR1 axis could limit G-MDSC migration, and depletion of Ly6G-positive cells could sensitize tumors to the combination of TH-302 and anti-VEGFR-2 with ICB. Together, these data suggest that pancreatic tumors modulate G-MDSC migration as an adaptive response to vascular normalization, and that these immunosuppressive myeloid cells act in a setting of persistent hypoxia to maintain adaptive immune resistance.
Arthur Liu, Seth T. Gammon, Federica Pisaneschi, Akash Boda, Casey R. Ager, David Piwnica-Worms, David S. Hong, Michael A. Curran
Poly (ADP-ribose) polymerase inhibitors (PARPis) are approved for cancer therapy according to their synthetic lethal interactions, and clinical trials have been applied in non–small cell lung cancer. However, the therapeutic efficacy of PARPis in lung adenocarcinoma (LUAD) is still unknown. We explored the effect of a mutated retinoblastoma gene (RB1) on PARPi sensitivity in LUAD. Bioinformatic screening was performed to identify PARPi-sensitive biomarkers. Here, we showed that viability of LUAD cell lines with mutated RB1 was significantly decreased by PARPis (niraparib, rucaparib, and olaparib). RB1 deficiency induced genomic instability, prompted cytosolic double-stranded DNA (dsDNA) formation, activated the cGAS/STING pathway, and upregulated downstream chemokines CCL5 and CXCL10, triggering immune cell infiltration. Xenograft experiments indicated that PARPi treatment reduced tumorigenesis in RB1-KO mice. Additionally, single-cell RNA sequencing analysis showed that malignant cells with downregulated expression of RB1 had more communications with other cell types, exhibiting activation of specific signaling such as GAS, IFN response, and antigen-presenting and cytokine activities. Our findings suggest that RB1 mutation mediates the sensitivity to PARPis through a synthetic lethal effect by triggering the cGAS/STING pathway and upregulation of immune infiltration in LUAD, which may be a potential therapeutic strategy.
Qi Dong, Tong Yu, Bo Chen, Mingyue Liu, Xiang Sun, Huiying Cao, Kaidong Liu, Huanhuan Xu, Yuquan Wang, Shuping Zhuang, Zixin Jin, Haihai Liang, Yang Hui, Yunyan Gu
The widely used chemotherapy cisplatin causes permanent hearing loss in 40-60% of cancer patients. One drug, sodium thiosulfate, is approved by the FDA for use in pediatric patients with localized solid tumors for preventing cisplatin-induced hearing loss, but more drugs are desperately needed. Here, we tested dabrafenib, an FDA-approved BRAF kinase inhibitor and anticancer drug, in a clinically relevant multi-dose cisplatin mouse model. The protective effects of dabrafenib, given orally twice daily with cisplatin, were determined by functional hearing tests and cochlear outer hair cells counts. Toxicity of the drugs co-treatment was evaluated, and levels of pERK were measured. Dabrafenib, in dose of 3 mg/kg/bw, twice daily, in mice, was determined to be the minimum effective dose and it is equivalent to one tenth of the daily FDA-approved dose for human cancer treatment. The levels of hearing protection acquired, 20-25 dB at the three frequencies tested, in both female and male mice, persisted for four months after completion of treatments. Moreover, dabrafenib exhibited a good in vivo therapeutic index (> 25), hearing protection in two different mouse strains, and diminished cisplatin-induced weight loss. Altogether, this study demonstrates that dabrafenib is a promising candidate drug for protection from cisplatin-induced hearing loss.
Matthew A. Ingersoll, Richard D. Lutze, Chithra K. Pushpan, Regina G. Kelmann, Huizhan Liu, Mark T. May, William J. Hunter, David Z.Z. He, Tal Teitz
Use of autologous cells isolated from elderly patients with multiple co-morbidities may account for the modest efficacy of cell therapy in patients with chronic limb threatening ischemia (CLTI). We aimed to determine whether pro-arteriogenic monocyte/macrophages (Mo/MΦs) from CLTI patients were functionally impaired and to demonstrate the mechanisms related to any impairment. Pro-arteriogenic Mo/MΦs isolated from CLTI patients were found to have an impaired capacity to promote neovascularization in vitro and in vivo compared with those isolated from healthy controls. This was associated with increased expression of human HIV-1 TAT interactive protein-2 (HTATIP2), a transcription factor known to suppress angiogenesis/arteriogenesis. Silencing HTATIP2 restored the functional capacity of CLTI Mo/MΦs which was associated with increased expression of arteriogenic regulators neuropilin-1 and angiopoietin-1, and their ability to enhance angiogenic (endothelial tubule formation) and arteriogenic (smooth muscle proliferation) processes in vitro. In support of the translational relevance of our findings, silencing HTATIP2 in pro-arteriogenic Mo/MΦs isolated from CLTI patients rescued their capacity to enhance limb perfusion in the ischemic hindlimb by effecting greater angiogenesis and arteriogenesis. Ex-vivo modulation of HTATIP2 may offer a strategy for rescuing the functional impairment of pro-angio/arteriogenic Mo/MΦs prior to autologous delivery and increase the likelihood of clinical efficacy.
Ashish S. Patel, Francesca E. Ludwinski, Angeles Mondragon, Katherine Nuthall, Prakash Saha, Oliver Lyons, Mario Leonardo Squadrito, Richard C. Siow, Michele De Palma, Alberto Smith, Bijan Modarai
New medicines are urgently required to treat the fatal neuromuscular disease, Duchenne muscular dystrophy (DMD). Dimethyl fumarate (DMF) is a potent immunomodulatory small molecule nuclear erythroid 2-related factor 2 (Nrf2) activator with current clinical utility in the treatment of multiple sclerosis and psoriasis that could be effective for DMD and rapidly translatable. Here, we tested two weeks of daily 100mg/kg DMF versus 5mg/kg standard care prednisone (PRED) treatment in juvenile mdx mice with early symptomatic DMD. Both drugs modulated seed genes driving the DMD disease program and improved force production in fast-twitch muscle. However, only DMF showed pro-mitochondrial effects, protected contracting muscles from fatigue, improved histopathology and augmented clinically compatible muscle function tests. DMF may be a more selective modulator of the DMD disease program than PRED warranting follow-up longitudinal studies to evaluate disease modifying impact.
Cara A. Timpani, Stephanie Kourakis, Danielle A. Debruin, Dean G. Campelj, Nancy Pompeani, Narges Dargahi, Angelo Patrick R. Bautista, Ryan M. Bagaric, Elya J. Ritenis, Lauren Sahakian, Didier Debrincat, Nicole Stupka, Patricia Hafner, Peter G. Arthur, Jessica R. Terrill, Vasso Apostolopoulos, Judy B. De Haan, Nuri Gueven, Dirk Fischer, Emma Rybalka
Hereditary spherocytosis (HS) is the most common non-immune hereditary chronic hemolytic anemia after hemoglobinopathies. The genetic defects in membrane function causing HS leads to perturbation of red cell metabolome, with altered glycolysis. In mice genetically lacking protein 4.2 (4.2-/-, Epb42), a murine model of HS, we show increased expression of pyruvate kinase (Pk) isoforms in whole and fractioned red cells in conjunction with abnormalities in the glycolytic pathway and in GSH system. Mitapivat, a PKs activator, metabolically re-programs 4.2-/- mouse red cells with amelioration of glycolysis and GSH cycle. This results in improved osmotic fragility, reduced phosphatidyl-serine (PS) positivity and decrease in erythroid vesicles release in vitro. Mitapivat treatment significantly decreases erythrophagocytosis and beneficially impacts iron homeostasis. In mild/moderate HS, the beneficial effect of splenectomy is still controversial. Here, we show that splenectomy improves anemia in 4.2-/- mice and that mitapivat is non-inferior to splenectomy. An additional benefit of mitapivat treatment is lower expression of markers of inflammatory vasculopathy in 4.2-/- mice with or without splenectomy, indicating a multi-systemic action of mitapivat. These findings support the notion that mitapivat treatment should be considered for symptomatic HS.
Alessandro Matte, Anand Babu Wilson, Federica Gevi, Enrica Federti, Antonio Recchiuti, Giulia Ferri, Anna Maria Brunati, Mario Angelo Pagano, Roberta Russo, Christophe Leboeuf, Anne Janin, Anna Maria Timperio, Achille Iolascon, Elisa Gremese, Lenny Dang, Narla Mohandas, Carlo Brugnara, Lucia De Franceschi
Overexpression of Phosphatases of Regenerating Liver 2 (PRL2), detected in numerous diverse cancers, is often associated with increased severity and poor patient prognosis. PRL2-catalyzed tyrosine dephosphorylation of the tumor suppressor PTEN results in increased PTEN degradation, and has been identified as a mechanism underlying PRL2 oncogenic activity. Overexpression of PRL2, coincident with reduced PTEN protein, is frequently observed in Acute Myeloid Leukemia (AML) patients. In the current study, a PTEN-knockdown AML animal model was generated to assess the impact of conditional PRL2 inhibition on the level of PTEN protein and the development and progression of AML. Inhibition of PRL2 resulted in a significant increase in median animal survival, from 40 weeks to greater than 60 weeks. The prolonged survival reflected delayed expansion of aberrantly differentiated hematopoietic stem cells into leukemia blasts, resulting in extended time required for clinically relevant leukemia blast accumulation in the bone marrow niche. Leukemia blast suppression following PRL2 inhibition was correlated with an increase in PTEN, and downregulation of AKT/mTOR regulated pathways. These observations directly established, in a disease model, the viability of PRL2 inhibition as a therapeutic strategy for improving clinical outcomes in AML and potentially other PTEN-deficient cancers by slowing cancer progression.
Colin Carlock, Yunpeng Bai, Allison Paige-Hood, Qinglin Li, Frederick Nguele Meke, Zhong-Yin Zhang
The combination of radiation therapy (RT) and immunotherapy has emerged as a promising treatment option in oncology. Historically, x-ray radiation (XRT) has been the most commonly used form of RT. However, proton beam therapy (PBT) is gaining recognition as a viable alternative, as it has been shown to produce similar outcomes to XRT while minimizing off-target effects. The effects of PBT on the antitumor immune response have only just begun to be described, and to our knowledge no studies to date have examined the effect of PBT as part of a combinatorial immunoradiotherapeutic strategy. Here, using a 2-tumor model of lung cancer in mice, we show that PBT in tandem with an anti-PD1 antibody substantially reduced growth in both irradiated and unirradiated tumors. This was accompanied by robust activation of the immune response, as evidenced by whole-tumor and single-cell RNA sequencing showing upregulation of a multitude of immune-related transcripts. This response was further significantly enhanced by the injection of the tumor to be irradiated with NBTXR3 nanoparticles. Tumors of mice treated with the triple combination exhibited increased infiltration and activation of cytotoxic immune cells. This triple combination eradicated both tumors in 37.5% of the treated mice and showed robust long-term immunity to cancer.
Yun Hu, Sébastien Paris, Narayan Sahoo, Genevieve Bertolet, Qi Wang, Qianxia Wang, Hampartsoum B. Barsoumian, Jordan Da Silva, Ailing Huang, Denaha J. Doss, David P. Pollock, Ethan Hsu, Nanez Selene, Claudia S. Kettlun Leyton, Tiffany A. Voss, Fatemeh Masrorpour, Shonik Ganjoo, Carola Leuschner, Jordan T. Pietz, Nahum Puebla-Osorio, Saumil Gandhi, Quynh-Nhu Nguyen, Jing Wang, Maria Angelica Cortez, James W. Welsh
Myotonic dystrophy type 1 (DM1), the most common form of adult-onset muscular dystrophy, is caused by a CTG expansion resulting in significant transcriptomic dysregulation that leads to muscle weakness and wasting. While strength training is clinically beneficial in DM1, molecular effects had not been studied. To determine whether training rescued transcriptomic defects, RNA-sequencing was performed on vastus lateralis samples from nine male DM1 patients before and after a 12-week strength training program and six male controls who did not undergo training. Differential gene expression and alternative splicing analysis were correlated with the one-repetition maximum strength evaluation method (leg extension, leg press, hip abduction, and squat). While training program-induced improvements in splicing were similar among most individuals, rescued splicing events varied considerably between individuals. Gene expression improvements were highly varied between individuals with the percentage of differentially expressed genes rescued after training strongly correlated with strength improvements. Evaluating transcriptome changes individually revealed responses to the training not evident from grouped analysis, likely due to disease heterogeneity and individual exercise response differences. Our analyses indicate that transcriptomic changes are associated with clinical outcomes in DM1 patients undergoing training and these changes are often specific to the individual and should be analyzed accordingly.
Emily E. Davey, Cécilia Légaré, Lori Planco, Sharon Shaughnessy, Claudia D. Lennon, Marie-Pier Roussel, Hannah K. Shorrock, Man Hung, John Douglas Cleary, Elise Duchesne, J. Andrew Berglund
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